Maytansinoids are potent anti-cancer compounds, the use of which is limited by their toxicity. One approach for managing the toxicity of these agents is to link the maytansinoid to an antibody that specifically targets the tumor. Antibody-maytansinoid conjugates have been shown to have potent anti-tumor activity in human xenograft studies (C. Liu et al., Proc. Natl. Acad. Sci. USA 93, 8618-8623 (1996)). MLN2704 is such a conjugate and is currently in Phase II clinical trials for the treatment of metastatic androgen independent prostate cancer. MLN2704 consists of a targeting monoclonal antibody vehicle (T-MAV) designed to deliver a lethal payload specifically to tumor cells that express on their surfaces prostate-specific membrane antigen (PSMA). In the case of MLN2704, the lethal payload consists of the chemotherapeutic maytansinoid DM1, which has been conjugated to the T-MAV. In preclinical studies, after binding to PSMA on the surface of a tumor cell, the T-MAV was transported inside the cell and the tumor cell was destroyed by the DM1. PSMA is expressed on almost all prostate cancer cells, both primary and metastatic, and its abundance on the cell surface increases as the cancer progresses. These findings suggest that MLN2704 has potential as a specific new therapy for prostate cancer. (See www.mlnm.com/rd/oncology/candidates/mln2704.asp).
DM1 has been prepared from maytansinol:
In the structure of DM1 shown above the chiral side chain in bold type may be attached to a linker group that connects the toxic maytansinoid and an antibody that is used to target the tumor. A two-step conversion of maytansinol to DM1 is known in the art (see U.S. Pat. No. 5,208,020). The first step is the coupling of maytansinol with N-methyl-N-(3-methyldithiopropanoyl)-L-alanine: HO2CCH(CH3)N(CH3)COCH2CH2SSMe, the preparation of which is described in U.S. Pat. No. 6,570,024. In the second step, the —SSMe group is reduced to the —SH group of DM1. A disadvantage of this synthesis is the epimerization of the side chain chiral center that occurs in the first step. Even under relatively mild coupling conditions (DCC and ZnCl2), complete epimerization occurs. Not only does the epimerization cause low yield of desired product, but the unwanted diastereomer must be removed by tedious chromatographic separation.
EP Patent Application Publication No. 0021173 describes the synthesis of maytansinol 3-(S)- and 3-(R)-α-N-methylaminopropionate from the corresponding maytansinol 3-α-(N-methyl-N-tert-butoxycarbonyl)aminopropionate. The latter compound was prepared by coupling maytansinol with N-tert-butoxycarbonyl-N-methyl-L-alanine in the presence of DCC. This coupling reaction provided low yields of both the 3-(S)- and 3-(R)-epimers.
Providing DM1 and other maytansinoids with chiral side chain linkers is costly. Starting maytansinol is expensive and the coupling reaction typically results in a low yield, largely because of epimerization when the side chain is attached in the coupling reaction. Accordingly, there is a need for higher yielding methods that avoid or reduce epimerization in the coupling of the side chain linker.